The long term goal of this project is the definition and characterization of factors regulating granulocyte production and maturation in humans as well as the definition of those alterations which occur in human hematopoietic disorders. Using the method of bone marrow culture in agar-gel by which single cells are stimulated to form colonies of maturing granulocytic and monocytic cells, factors affecting granulocyte and monocyte production and maturation are studied. The specific aims are to determine the nature of the signal for production of granulopoietic factors by the monocyte-macrophage system. Initial work suggests that this signal may arise from the granulocytes themselves. Further studies are aimed at determining the biochemical nature of these granulopoietic substances and their mechanism of action. Human leukemias are under intense study to determine whether the alterations in granulopoietic factors which have been described in these disorders can be manipulated therapeutically. Human aplastic anemia and granulocytopenic states are being studied for alterations in granulopoietic regulation, and animal models of these conditions are also under study with the same aims in mind. Alterations in levels of granulocyte regulators are also being studied in post-operative infections in man and in induced sepsis in dogs. Inhibitors of granulopoietic factors and determination of their specificity are under investigation in lymphoblastic disorders and in normal humans. Li2CO3, a drug known to induce granulocytosis in hematologically normal humans, is being studied for its effect on granulocyte production in vitro in an attempt to determine its method of action and possible therapeutic usefulness in granulocyte disorders. The relationship between granulopoietic factors and B12 binding proteins in serum, urine, and tissues is under investigation.